Retinoic acid receptor-α up-regulates proopiomelanocortin gene expression in AtT20 corticotroph cells

Akira Uruno, Akiko Saito-Hakoda, Atsushi Yokoyama, Naotaka Kogure, Ken Matsuda, Rehana Parvin, Kyoko Shimizu, Ikuko Sato, Masataka Kudo, Takeo Yoshikawa, Hiroyuki Kagechika, Yasumasa Iwasaki, Sadayoshi Ito, Akira Sugawara

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Cushing’s disease is a disorder caused by excessive ACTH secretion from a corticotroph tumor of the pituitary gland. Although its standard therapy is a transsphenoidal surgery, innovation of novel medical treatments for the disease is urgently necessary. Retinoic acid (RA) has been reported to suppress adrenocorticotropic hormone (ACTH) secretion in Cushing’s disease. However, the role of RA receptor (RAR) in proopiomelanocortin (Pomc) gene expression remains uncertain. We here examined the involvement of RARα in Pomc regulation using AtT20 corticotroph cells. Surprisingly, a synthetic RARα agonist Am80 increased Pomc mRNA expression, CRH-induced ACTH secretion, and Pomc promoter activity. Small interfering RNA-mediated RARα-knockdown suppressed both basal and Am80-induced Pomc promoter activity. RARα-overexpression dose-dependently increased Pomc promoter activity. Pomc promoter mutation analysis revealed that both Tpit and NeuroD1 binding elements were responsible for the Am80-mediated effect. Am80 increased Tpit expression while RAR antagonist LE540 suppressed the increase. Tpit-overexpression increased Pomc promoter activity. Mammalian two-hybrid assay revealed that Am80 induced NeuroD1-RARα interaction. NeuroD1-overexpression enhanced the Am80-induced Pomc promoter activity, which was suppressed by NeuroD1 truncated mutant-overexpression. RARα thus positively regulates ACTH secretion/Pomc gene expression through interaction with NeuroD1 and Tpit expression increase. The present observation will be useful for the future development of the RA/retinoid-derived therapeutics of the disease.

Original languageEnglish
Pages (from-to)1105-1114
Number of pages10
Journalendocrine journal
Volume61
Issue number11
DOIs
Publication statusPublished - 2014

Keywords

  • ACTH
  • Pomc
  • RARα

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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